A case series of eosinophilic myocarditis: different faces of the same coin.

Background: Eosinophilic myocarditis (EM) is a rare form of myocarditis with various aetiologies and dire consequences if not diagnosed and treated expeditiously. Case summary: We report three cases of EM at different stages of the disease with differing clinical manifestations. We highlight the diagnostic workup including the role of multimodality imaging and endomyocardial biopsy (EMB), and the treatment strategies. Discussion: EM is an underdiagnosed and potentially life-threatening disease. Therefore, a high clinical suspicion for EM should arise when patients with signs and symptoms of cardiovascular disease develop hypereosinophilia or vice versa. Early identification of this condition using multimodality imaging and EMB is of paramount importance as the disease may progress to the irreversible late fibrotic stage if treatment is delayed.

Re-induction versus salvage for D14-resiudal acute myeloid leukemia: A retrospective multi-center study.

Remission assessment in acute myeloid leukemia has evolved over the recent years with the advent of molecular and flow-based minimal residual disease determination. Nonetheless, early time point such as day 5 and day 14 (D14), still have prognostic and therapeutic implications. D14 refractory disease is regarded as a poor prognostic factor, however the therapeutic intervention is still under debate, with evidence suggesting a successful re-induction might offer similar long-term outcome as D14 aplasia. Others advocate the use of more intensive salvage protocols as a mean to overcome the negative prognostic effect. In the current study, we compare outcome of D14 refractory AML patients treated with either re-induction or salvage protocol. More importantly, we identify response characteristics that might suggest which patients will benefit from re-induction approach. Accurate identification of chemotherapy refractory patients might allow the early incorporation of non-chemotherapy based protocols in the future.

Rituximab, methotrexate, procarbazine and lomustine (R-MPL) for the treatment of primary Central nervous system lymphoma.

The optimal high-dose methotrexate (HDMTX)-based combination therapy for primary central nervous system lymphoma is unknown. We report our experience with rituximab, HDMTX, procarbazine and lomustine (R-MPL) given as first-line treatment in our center. Fifty-two patients between 2006 and 2019 were included. Eighteen patients proceeded to autologous transplant or two cycles of intermediate-dose cytarabine. The median age was 62 y (range 28-94) and the Eastern Cooperative Oncology Group performance status (ECOG-PS) was ≥2 in 62% (32/52). The overall/complete response rates were 79% (41/52) and 52% (27/52), respectively. The median progression-free/overall survival was 19 m/84m, respectively. Grade 3-4 adverse events included infections (17%) and kidney injury (13%). Ten patients (19%) discontinued therapy for toxicity. There were no treatment-related deaths. In summary, in a cohort enriched in frail patients, R-MPL achieved good responses and OS and was safe for all ages. The PFS was sub-optimal, possibly explained by a low proportion of consolidation. This regimen should be evaluated prospectively.

Venetoclax combinations induce high response rates in newly diagnosed acute myeloid leukemia patients ineligible for intensive chemotherapy in routine practice.

Combinations of the BCL-2 inhibitor, venetoclax, with either hypomethylating agents (HMA) or low dose cytarabine (LDAC), have shown promising results in clinical trials of AML patients unfit for intensive therapy. We report on the efficacy and safety of venetoclax combinations in AML patients treated outside of clinical trials. Complete remission (CR) + CR with incomplete count recovery (CRi) were achieved in 61% of patients, with similar CR+CRi rates in with secondary AML, and in patients who were previously treated with HMA (61% and 43%, respectively). Relapse occurred in 25% of patients, with a median event-free survival (EFS) of 11.7 months (95% CI, 10.09-13.35) in responding patients. At a median follow up of 8.7 months, the median overall survival (OS) was 9.8 months (95% CI 6.42-13.3) in the entire cohort. In multivariate analysis adverse karyotype was the only negative predictor of CR/CRi (p = .03), while both ECOG performance status (PS) and adverse karyotype were significantly associated with shorter OS (p = .023 and .038, respectively). Median OS was higher in patients achieving CR/CRi and in patients proceeding to allogeneic stem cell transplantation (allo-SCT). Treatment was well tolerated, with side effects similar to those described in the randomized clinical trials. Tumor lysis syndrome (TLS) occurred in 12% of patients. Our data support the efficacy and safety of venetoclax combinations in newly diagnosed AML patients not eligible for intensive therapy. According to our data, secondary AML patients could benefit from venetoclax combinations similarly to de-novo AML patients, and allo-SCT could be offered to selected patients achieving CR/CRi.

Diagnostic and Management Difficulty of Bleeding Aorto-Duodenal Fistula Associated with Hodgkin's Lymphoma.

Primary aorto-enteric fistula (AEF) resulting from abdominal malignancy is a rare and often fatal complication. The few reports to date are mostly secondary to solid tumors. We present a case of a patient with refractory Hodgkin's lymphoma who developed life-threatening AEF. We describe the diagnostic and therapeutic efforts, requiring a multi-disciplinary team of interventional radiology, gastroenterology, and transfusion medicine, resulting in a favorable outcome. Importantly, we offer several insights regarding the identification and management of high-risk patients, with an emphasis on pre-treatment considerations and urgent diagnosis and intervention.

Venetoclax is safe and efficacious in relapsed/refractory AML.

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.

Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia.

Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life-threatening toxicity. The bispecific T-cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B-cell depletion, the safety of its use during severe chemotherapy-induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy-associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.

Romidepsin-Bendamustine Combination for Relapsed/Refractory T Cell Lymphoma.

BACKGROUND: The treatment of relapsed/refractory (R/R) peripheral T cell lymphoma (PTCL) is limited to a few agents. Romidepsin, a histone deacetylase inhibitor, was approved for PTCL treatment as a single agent in the R/R setting, yet with partial efficacy. Several attempts to combine romidepsin with other chemotherapy regimens have been reported, however, with significant toxicity. OBJECTIVES: To study the romidepsin-bendamustine combination in PTCL in an attempt to maximize efficacy while minimizing toxicity. METHODS: We report on a series of 7 heavily pretreated PTCL patients (2-5 previous lines of therapy) treated with a romidepsin-bendamustine combination. RESULTS: Four patients were not previously exposed to either drug. Of these, 2 achieved complete remission. Interestingly, 1 patient continued treatment with a prolonged progression-free survival of more than 4 years. Toxicity was minimal and no treatment-related deaths or discontinuation were noted. Significant nausea and vomiting were reported in over 50% of patients. Hematological toxicity was mild and lower than that reported for other romidepsin-chemotherapy combinations and was correlated with bone marrow involvement by lymphoma. CONCLUSIONS: Although reporting a small number of patients, our data suggest that the combination of romidepsin and bendamustine may be a feasible therapeutic option in R/R PTCL patients and merits further study.

A Bortezomib-Based Protocol Induces a High Rate of Complete Remission with Minor Toxicity in Adult Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

The treatment of relapsed/refractory acute lymphoblastic leukemia (RR-ALL) presents a true clinical challenge. In 2012, a protocol combining bortezomib, dexamethasone, asparaginase, doxorubicin, and vincristine administered to children with RR-ALL was published with encouraging results. Over the past 5 years, we have implemented this protocol in the adult RR-ALL population (> 18 years) and addressed its feasibility in terms of remission rate and toxicity. Here, we present the results of our experience in 9 patients, all of whom received multiple previous chemotherapy protocols, two of them relapsing after an allogeneic bone marrow transplantation. All of the five B-ALL patients, and two of the four T-ALL achieved complete remission. Of the seven patients achieving complete remission, two patients were referred for allogeneic bone marrow transplantation, two patients were subsequently given blinatumomab, and one patient subsequently received donor lymphocyte infusion followed by blinatumomab. Thus, five out of nine patients treated (55%) were able to proceed to best available therapy in a complete remission. We observed minimal adverse effects, mainly hematological toxicity. We conclude that the bortezomib-based protocol should be evaluated as an effective and well-tolerated treatment option for adult patients either unfit for or failing standard salvage chemotherapy, as a bridge to immunotherapy or allogeneic bone marrow transplantation.

Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis.

OBJECTIVE: Daratumumab is a promising new antimyeloma agent. We report a single center "real-world" series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab. METHODS: Forty-one patients were included: 7 second-line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL. RESULTS: Second-line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression-free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti-CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab. CONCLUSIONS: Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.

Alopecia Areata as a Manifestation of Systemic Lymphoma: Report of Two Cases.

Alopecia areata is a common autoimmune disorder leading to hair loss. It usually affects individuals under the age of 40, and first appearance in older subjects is considered uncommon. Here, we report 2 cases of rapidly progressing alopecia areata, which appeared for the first time in adults. Patient 1 had alopecia universalis, which preceded the identification of hepatosplenic T-cell lymphoma, a rare form of lymphoma. Patient 2 suffered from the ophiasis type of alopecia areata, presenting for the first time following chemotherapy for non-Hodgkin B-cell lymphoma. These 2 cases highlight the need to screen for malignancies in patients who present with rapidly progressing alopecia areata for the first time after the age of 40.

A Randomized Controlled Study to Determine the Efficacy of Garlic Compounds in Patients With Hematological Malignancies at Risk for Chemotherapy-Related Febrile Neutropenia.

BACKGROUND: Patients receiving chemotherapy for hematological malignancies are at high risk for febrile neutropenia (FN). Garlic extracts (GEs) are natural food substances showing antimicrobial effects in vivo. OBJECTIVES: We explored whether adding GE may be efficacious in reducing the risk or severity of infections. DESIGN: This was a placebo-controlled double-blind randomized study. RESULTS: Of 95 patients randomized to receive GE or placebo following chemotherapy, a febrile episode was documented in 50% of patients receiving GE and 63.3% receiving placebo (P = .89). There was a higher risk of developing a third and fourth febrile episode in the GE group (P = .01). However, among those at a lower risk for FN, those receiving GE developed fewer FN episodes (P = .075), especially those with severe neutropenia (P = .05). Major adverse events were distributed equally, but nonadherence was more common in the GE than in the placebo group: 19.5% versus 4%, respectively (P = .05). CONCLUSIONS: GE was safe and did not reduce FN risk in the entire cohort, but yet appeared to exert a protective effect in the lower-risk subgroup. We do not recommend the use of GE for FN prevention in higher-risk patients. A larger-scale clinical trial for the lower-risk subgroup of patients is advocated. (This trial was registered at www.clinicaltrials.gov as NCT00247039.).

Clinical considerations and key issues in the management of patients with Erdheim-Chester Disease: a seven case series.

BACKGROUND: Erdheim-Chester Disease (ECD), a non Langerhans' cell histiocytosis of orphan nature and propensity for multi-systemic presentations, comprises an intricate medical challenge in terms of diagnosis, treatment and complication management. OBJECTIVES: The objectives are to report the clinical, radiological and pathological characteristics, as well as cardinal therapeutic approaches to ECD patients and to provide clinical analyses of the medical chronicles of these complex patients. METHODS: Patients with biopsy proven ECD were audited by a multi-disciplinary team of specialists who formed a coherent timeline of all the substantial clinical events in the evolution of their patients' illness. RESULTS: Seven patients (five men, two women) were recruited to the study. The median age at presentation was 53 years (range: 39 to 62 years). The median follow-up time was 36 months (range: 1 to 72 months). Notable ECD involvement sites included the skeleton (seven), pituitary gland (seven), retroperitoneum (five), central nervous system (four), skin (four), lungs and pleura (four), orbits (three), heart and great vessels (three) and retinae (one). Prominent signs and symptoms were fever (seven), polyuria and polydipsia (six), ataxia and dysarthria (four), bone pain (four), exophthalmos (three), renovascular hypertension (one) and dyspnea (one). The V600E BRAF mutation was verified in three of six patients tested. Interferon-α treatment was beneficial in three of six patients treated. Vemurafenib yielded dramatic neurological improvement in a BRAF mutated patient. Infliximab facilitated pericardial effusion volume reduction. Cladribine improved cerebral blood flow originally compromised by perivenous lesions. CONCLUSIONS: ECD is a complex, multi-systemic, clonal entity coalescing both neoplastic and inflammatory elements and strongly dependent on impaired RAS/RAF/MEK/ERK signaling.

Polymorphisms in the human organic cation transporter and the multidrug resistance gene: correlation with imatinib levels and clinical course in patients with chronic myeloid leukemia.

The optimal tyrosine kinase inhibitor for any individual patient with chronic myeloid leukemia (CML) is not predictable. Pharmacogenetic parameters and trough levels of imatinib (IM) have each been independently correlated with response. We therefore studied the human organic cation transporter (hOCT1) and multidrug resistance (MDR1) single nucleotide polymorphisms (SNPs) and correlated these with IM levels and major molecular response (MMR) (3-log reduction) in 84 patients with CML, the first such study performed in Caucasians. We studied MDR1 G2677T and C3435T, and for hOCT1, C480G and A1222G. IM levels varied significantly with dose (< or > 400 mg/day) (p = 0.038) and were significantly lower in 20 patients who lost MMR (p = 0.042). Adjusting for dose, trough IM levels were not significantly correlated with SNPs. Patients with MDR1 3435 TT had significantly longer times to MMR compared to CC/CT genotypes (p = 0.047). Genotypes did not predict treatment failure when controlling for IM levels. We conclude that IM levels, but not the SNPs studied here, determine IM failure.

Short communication: bendamustine-related hemolytic anemia in chronic lymphocytic leukemia.

PURPOSE: Immune hemolytic anemia (IHA) may complicate the course of chronic lymphocytic leukemia (CLL), especially in patients with advanced disease, and as a complication of treatment with chlorambucil or fludarabine. Bendamustine, a novel agent with both alkylating and purine-analog properties, was approved in the USA for use in CLL in 2008. Since then, clinical data on its adverse events are accumulating. IHA related to bendamustine was seldom described and is thus reported and reviewed. METHODS: We assessed five cases of CLL patients complicated by IHA, out of 31 treated with bendamustine for a relapse of their disease. Also reviewed are previous case reports in the literature. RESULTS AND CONCLUSIONS: Bendamustine-related IHA is more common than suspected (16 %). No such cases were found in non-CLL patients. Personal history of fludarabine-triggered AIHA may be a risk factor for this complication (recorded in 4/5 patients, 80 %). The mechanism is thought to be related to the loss of T cell regulatory control as described for other agents. Physicians using bendamustine for the treatment for CLL should be aware of this complication.

The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation.

The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34(+) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.

Methylation of RUNX1 by PRMT1 abrogates SIN3A binding and potentiates its transcriptional activity.

RUNX1/AML1 is required for the development of definitive hematopoiesis, and its activity is altered by mutations, deletions, and chromosome translocations in human acute leukemia. RUNX1 function can be regulated by post-translational modifications and protein-protein interactions. We show that RUNX1 is arginine-methylated in vivo by the arginine methyltransferase PRMT1, and that PRMT1 serves as a transcriptional coactivator for RUNX1 function. Using mass spectrometry, and a methyl-arginine-specific antibody, we identified two arginine residues (R206 and R210) within the region of RUNX1 that interact with the corepressor SIN3A and are methylated by PRMT1. PRMT1- dependent methylation of RUNX1 at these arginine residues abrogates its association with SIN3A, whereas shRNA against PRMT1 (or use of a methyltransferase inhibitor) enhances this association. We find arginine-methylated RUNX1 on the promoters of two bona fide RUNX1 target genes, CD41 and PU.1 and show that shRNA against PRMT1 or RUNX1 down-regulates their expression. These arginine methylation sites and the dynamic regulation of corepressor binding are lost in the leukemia-associated RUNX1-ETO fusion protein, which likely contributes to its dominant inhibitory activity.

A trifungal infection of the mandible: case report and literature review.

Orofacial fungal infections are occasionally seen in the immunocompromised patient. In this case, a patient with a relapse of an acute lymphoblastic leukemia (ALL) developed a fatal mandibular infection. This may be the first reported case of a trifungal infection with zygomycosis, aspergillosis, and candidiasis in the oral cavity and the fifth mandibular zygomycosis case. Epidemiology, diagnosis, treatment and prognosis of zygomycosis infection are reviewed, along with the 4 mandibular zygomycosis cases found in the English literature.

A new point-of-care method for monitoring anti-platelet therapy: application of the cone and plate(let) analyzer.

Recent studies suggest that anti-platelet agents are not equally effective in all individuals. We have developed a new method to evaluate the effect of anti-platelet drugs using the cone and plate(let) analyzer (CPA) test. The method is based on the ability of activators to reduce platelet adhesion under flow conditions. Treatment of a blood sample with arachidonic acid (AA) or ADP in vitro significantly decreased platelet deposition to a surface coverage (SC) of 2.1+/-0.4 and 1.3+/-0.6%, respectively, compared with the basic SC of 12.3+/-6.8%. The effect of AA was prevented by aspirin (SC 8.1+/-3.8%) and that of ADP was reduced by 2-methylthio-AMP, a P2Y12 ADP receptor inhibitor (SC 4.8+/-2.0%). Pre-incubation with AA of whole blood samples from untreated healthy volunteers resulted in a marked decline of SC (from SC 9.8+/-2.2 to 0.6+/-0.3%). In contrast, in volunteers treated with 100, 300, and 500 mg aspirin per day, AA (but not ADP) decreased SC only to 3.5+/-1.3, 4.4+/-1.7, and 4.1+/-2.0%, respectively (P<0.001 versus SC with AA before treatment). A good correlation was observed between the modified CPA and aggregometry (R2=0.55). In conclusion, the modified CPA test is a useful tool to evaluate the efficacy of anti-platelet therapy.

Prolonged fever of unknown origin and hemophagocytosis evolving into acute lymphoblastic leukemia.

Hemophagocytic syndrome (HPS) is an unusual acute syndrome presenting with fever, hepatosplenomegaly, and cytopenias. The hallmark of HPS is the accumulation of activated macrophages that engulf hematopoietic cells in the reticuloendothelial system. Most cases of HPS in adults are secondary to infection or malignancy, and thus investigation of the underlying disease is necessary. We describe a patient with prolonged fever, HPS, and chromosomal abnormalities in the bone marrow who underwent thorough evaluation for the cause of his symptoms. A final diagnosis of acute lymphoblastic leukemia (ALL) was established in a fourth, repeated bone marrow biopsy performed more than 2 months after the first presenting symptom appeared. This unusual case demonstrates the importance of cytogenetic abnormalities found in cases of HPS and the importance of repeated testing when an underlying disease is suspected.